Submissions for variant NM_000535.7(PMS2):c.1204C>T (p.Gln402Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002344708	SCV002654107	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-14	criteria provided, single submitter	clinical testing	The p.Q402* pathogenic mutation (also known as c.1204C>T), located in coding exon 11 of the PMS2 gene, results from a C to T substitution at nucleotide position 1204. This changes the amino acid from a glutamine to a stop codon within coding exon 11. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003454169	SCV004187692	pathogenic	Lynch syndrome 4	2023-09-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV004017926	SCV004848601	likely pathogenic	Lynch syndrome	2021-11-23	criteria provided, single submitter	clinical testing	The p.Gln402X variant in PMS2 has not been reported in individuals with PMS2-associated cancers or in large population studies. This nonsense variant leads to a premature termination codon at position 402, which is predicted to lead to a truncated or absent protein. Loss of function of the PMS2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.